We continue to improve our understanding of the pathogenesis of pre-malignant monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM), as summarized below. First, we have shown that MM tumors mostly - if not always - is preceded by MGUS. Significantly, in four patients, the MM and preceding MGUS tumors were light chain only, confirming that light chain only MGUS is a significant clinical entity, and suggesting that light chain only MM usually is preceded by light chain only MGUS and not MGUS that loses expression of IgH chains. Second, we have identified seven primary translocation partners that are present in 40% of multiple myeloma tumors and comprise three translocation groups: CYCLIN D, MAF, and MMSET/FGFR3. Third, we determined that the dysregulation of a CYCLIN D gene is an early and unifying event in MGUS and multiple myeloma. Fourth, these two early oncogenic events enabled us to propose the TC (translocation/cyclin D) classification, which appears to be applicable to all MGUS and multiple myeloma tumors, but also has been demonstrated to have significance for therapeutic decisions. Fifth, we have determined that secondary translocations, which are involved in tumor progression, have structural features and chromosomal partners that distinguish them from primary translocations. Sixth, we have determined that NFKB activation either by extrinsic ligands or by mutations in at least nine components of the classical and/or alternative NFKB pathways is important for the survival and growth of normal plasma cells as well as most MGUS and MM tumors. This suggests that MGUS and MM tumors may be addicted to this pathway, and thus sensitive to drugs that inhibit the NFKB pathway. Seventh, we have identified a RAS paradox, i.e., N-RAS mutations were identified in 14% of MM tumors and4 of 51 (8%) MGUS tumors, but K-RAS mutations were identified in 17% of MM tumors but none the 51 MGUS tumors. It seems that K- and N-RAS are not interchangeable but actually have different roles in the pathogenesis of MM, a result that is consistent with recent reports by others that K- and N-RAS are not functionally equivalent. Eighth, we have determined that the PI3K/AKT pathway is activated in at least 20% of MM tumors, usually by overexpression of DEPTOR induced by MAF and yet to be identified mechanisms, and less often by inactivation of PTEN. Ninth, inactivation or mutation of p53 and additional disruption (beyond the early dysregulation of a CYCLIN D gene) of the RB pathway appear to be relatively late progression events that are associated with increased proliferation and a poor prognosis. The RB pathway alterations are manifested by homozygous deletion of p18INK4c (10-30% of proliferative tumors and cell lines) vs an increase in the expression of p18 (60% of cell lines and proliferative tumors); this increase probably results from the fact that E2F enhances transcription of genes that increase proliferation, but also of p18. The insensitivity of the RB pathway to the inhibitory effects of p18 remains unexplained except for a small fraction of tumors that have inactivated RB1. Finally, and most recently, we have determined that cryptic rearrangements in the MYC locus that are detected by CGH, usually without involvement of an Ig locus, are present in 46% of newly diagnosed and 51% of previously treatedMM tumors (see below for further details). Research accomplishments that resulted in publication in 2014 included: 1) demonstration that genomic rearrangements in the MYC locus are the most prevalent rearrangement in MM, and that they often occur relatively early in the pathogenesis of MM, although some MYC locus rearrangements still occur as late progression events. MM tumors with the cryptic MYC locus rearrangements have a significantly higher expression level of MYC (mostly monoallelic expression) than tumors not having a detectable rearrangement (which mostly have biallelic expression). This new evidencefor early MYC rearrangements in some MM tumors is consistent with the increased expression of MYC in MM vs pre-malignant MGUS tumors, even for MM tumors lacking evidence of MYC rearrangement. This data also is consistent with a published animal model in which conditional dysregulation of a MYC transgene results in a high incidence of MM in an MGUS-prone mouse strain. Our new working hypothesis is that increased MYC expression, which is associated with cryptic rearrangements in the MYC locus in 50% of MM tumors but by yet to be identified trans mechanisms in the other half of MM tumors is an essential event involved in the progression of pre-malignant MGUS to MM. Our prior results showing that MYC locus rearrangements often are late events suggests an additional hypothesis: tumors that have increased expression of MYC by a trans mechanism often acquire a late rearrangement of the MYC locus as the tumors become more aggressive and less dependent on the bone marrow microenvironment. 2) demonstration that novel MAP3K14 (NFkappaB kinase [NIK]) inhibitors are selectively toxic for myeloma cell lines that have mutations that cause NIK-dependent activation of the NFkappaB pathway; 3) development of an assay that can determine the fraction of monoclonal tumor B cells (lymphocyte, plasma cells) in patient samples isolated for molecular analyses; 4) demonstration that the commercial Vysis FISH probes, which have been used in most clinical studies for IGH rearrangements, frequently miss secondary IGH rearrangements (mostly IGH insertions). By contrast, our in-house IGH probes and commercial Cytocell IGH probes detect most secondary IGH rearrangements1 5) we contributed to research showing that the combination of mTor and class I HDAC inhibitors synergistically the proliferation and/or survival of MM cell lines and primary MM tumor cells 6) we contributed to research showing that genetic inactivation of STK4 restores YAP1 levels, triggering cell death of MM cells, a result that identifies a novel synthetic -lethal strategy to selectively target MM cell presenting with endogenous DNA damage and low YAP1 levels.